CN102702302B - Tanshinone class I derivant and synthesizing method and application thereof - Google Patents
Tanshinone class I derivant and synthesizing method and application thereof Download PDFInfo
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Abstract
The invention relates to a tanshinone class I derivant and a synthesizing method and an application thereof, wherein the tanshinone class I derivant is characterized in that various substituent groups are introduced into different positions of a ring A of a tanshinone I molecule, the number of carbonyl groups on a ring C of the tanshinone I molecule is selectively retained, and a ring D of the tanshinone I molecule is reduced into a dihydrofuran ring. The preparation method comprises the steps that Diels-Alder reaction is carried out on a styrene compound and p-benzoquinone, and a key skeleton--phenanthraquinone compound is obtained after separation and purification; and then the phenanthraquinone compound is reacted with enamine to introduce a furan ring into the phenanthraquinone skeleton, and a target product--tanshinone class I compound is obtained through acidizing hydrolysis, oxidation reaction, separation and purification, and the tanshinone class I compound is catalytically hydrogenated to obtain a dihydro tanshinone class I compound. Cytotoxicity research and pharmacology research results show the cytotoxicity of the compound, so that the tanshinone compound has wide clinical application prospects, and is expected to be used as a new antineoplastic medicine.
Description
Technical field
The present invention relates to pharmaceutical technology field, especially one is prepared antineoplastic Tanshinone I derivative and its preparation method and application.
Background technology
The red sage root is the dry root and rhizome of the labiate red sage root (SALVIA MILTIORRHIZA BUNGE), begins to be loaded in Shennong's Herbal, is used as medicine with a long history.Red sage root bitter, micro-pungent, cold nature, the thoughts of returning home, Liver Channel, have the effect of stasis-dispelling and pain-killing, promoting blood circulation to restore menstrual flow, nourishing blood to tranquillize the mind, the detumescence of cool blood.
Along with the develop rapidly of the technological methods such as chemistry, molecular biology, people also deepen continuously to the research of salviamiltiorrhizabung complicated chemical composition.According to existing result of study, the red sage root is made up of fat-soluble and water-soluble two class chemical compositions.Wherein, tanshinone Ⅰ, II A, II B, Cryptotanshinone, dihydrotanshinone Ⅰ etc. are the main effective constituent of the red sage root, in the clinical treatment of the cardiovascular disordeies such as hypertension, coronary artery disease, myocardial infarction, cerebral thrombosis, play a significant role.Research shows, TANSHINONES has natural anti-oxidation effect, can reduce calcium overload, suppress the activation of neutrophil leucocyte and apoptosis of cardiac muscle, removing oxyradical, thereby plays control reperfusion injury of cardiac muscle, reduce the effect of brain injury; The o-quinone of tanshinone or para-quinoid structure easily and its diphenols derivative generation change, cause Electron Transfer in redox transition process; The effects such as meanwhile, its meta-bolites easily participates in multiple biochemical reaction as the coenzyme of biological respinse, and main manifestations is antisepsis and anti-inflammation.In addition, TANSHINONES also there is promoting blood circulation to restore menstrual flow, improve liver microcirculation, gentle estrogen-like effects and the central nervous system restraining effect such as calm.In recent years, along with deepening continuously of TANSHINONES pharmacological research, its widely anti-tumor activity be it is found that gradually, and become new study hotspot.
But, now obtaining at present tanshinone compound is mainly by extracting natural tanshinone compound in the rear separation red sage root, its utilization clinically that had following drawbacks limit in the time of research tanshinone compound pharmaceutical active: 1. TANSHINONES single compound is extracted and separated necessary Integrated using and adsorbs from natural phant, precipitation, extraction, the multinomial technology such as ion-exchange and chromatogram, its yield is very low, and cost cost is too high.2. naturally occurring tanshinone compound is most water-soluble extremely low, orally uses bioavailability lower; Also be difficult to make other suitable form of administration simultaneously.3. the problems the such as at present route of synthetic tanshinone compound all exists that cost is higher, severe reaction conditions, route are partially long, big for environment pollution.
Summary of the invention
The present invention is taking Tanshinone I as lead compound, design and synthesize out series of new compound, it is characterized in that introducing various types of substituting groups on the different positions of Tanshinone I molecule A ring, optionally retain the quantity of the carbonyl on Tanshinone I molecule C ring, and Tanshinone I molecule D ring is reduced to dihydrofuran ring; Anticancer Activity in vitro experiment (mtt assay) research shows, the compounds of this invention all shows the inhibited proliferation to tumour cell, the activity of part of compounds is better than or equals positive control medicine white arsenic, show through preliminary pharmacological tests, the compounds of this invention all has restraining effect in various degree to nude mice tumour cell heteroplastic transplantation model and mouse tumor model.
Simultaneously the present invention also provides a kind of method simple, does not affect environment, process stabilizing, and be suitable for the method for preparing Tanshinone I analog derivative of suitability for industrialized production.
The general structure of the compounds of this invention as shown in the formula:
Tanshinone I analog derivative general formula I
Wherein R
1~ R
4represent: substituting group can have 4 identical or different substituting groups on A ring;
R
1~ R
4the substituting group of representative is: hydrogen, chlorine, bromine, iodine, fluorine, methoxyl group, oxyethyl group, allyloxy, amino, the monosubstituted amido of C1 ~ C4 alkyl, C1 ~ C4 alkyl bis substituted amine base, C0 ~ C4 alkyl (replacement) phenyl amido, C0 ~ C4 alkyl (replacement) benzyl base amido, 1-morpholinyl, piperidyl, kharophen, , N-urea groups, N-thioureido, guanidine radicals, nitro, trifluoromethyl, cyano group, ethanoyl, C1 ~ C4 alkyl sulphonyl, amino-sulfonyl, C1 ~ C4 alkylamino radical alkylsulfonyl, allyl amido alkylsulfonyl, morpholine-1-base alkylsulfonyl, piperidines-1-1 base alkylsulfonyl,
D ring is dihydrofuran or furan nucleus.
2. the compound of claim 1, R
1~ R
4substituting group can represent identical substituting group simultaneously, also can represent separately not identical substituting group simultaneously.
3. the compound of claim 1, wherein R
1~ R
4representative: hydrogen, chlorine, bromine, iodine, fluorine, methoxyl group, oxyethyl group, allyloxy, amino, C
1~ C
4the monosubstituted amido of alkyl, C1 ~ C4 alkyl bis substituted amine base, C0 ~ C4 alkyl (replacement) phenyl amido, C
0~ C
4alkyl (replacement) benzyl base amido, 1-morpholinyl, piperidyl, kharophen.
4. the compound of claim 3, wherein R
1~ R
4representative: hydrogen, iodine, methoxyl group, oxyethyl group, allyloxy, amino, C
1~ C
4the monosubstituted amido of alkyl, C
1~ C
4alkyl bis substituted amine base 1-morpholinyl, piperidyl, kharophen.
5. the compound of claim 4, wherein R
1~ R
4representative: hydrogen, amino, C
1~ C
4the monosubstituted amido of alkyl, C
1~ C
4alkyl bis substituted amine base 1-morpholinyl, piperidyl.
6. the compound pharmacy acceptable salt of claim 5, wherein pharmacy acceptable salt is compound of Formula I and following sour salify: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, carbonic acid, citric acid, tartrate, lactic acid, pyruvic acid, acetic acid, toxilic acid, fumaric acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid.
Part of compounds of the present invention is:
The chloro-benzene phenanthro-of 3-methyl-8-[3,2-c] furans-1,2-diketone (I-2) (code name II-1, lower same)
The bromo-benzene phenanthro-of 3-methyl-8-[3,2-c] furans-1,2-diketone (I-3)
The chloro-benzene phenanthro-of 3-methyl-9-[3,2-c] furans-1,2-diketone (I-4)
The bromo-benzene phenanthro-of 3-methyl-9-[3,2-c] furans-1,2-diketone (I-5)
3-methyl-9-methoxyl group-benzene phenanthro-[3,2-c] furans-1,2-diketone (I-6)
3-methyl-9-amino-benzene phenanthro-[3,2-c] furans-1,2-diketone (I-8)
3-methyl-9-(N-2-methyl)-benzene phenanthro-[3,2-c] furans-1,2-diketone (I-9)
3-methyl-9-acetylaminohydroxyphenylarsonic acid benzene phenanthro-[3,2-c] furans-1,2-diketone (I-10)
3-methyl-9,10-dimethoxy-benzene phenanthro-[3,2-c] furans-1,2-diketone (I-11)
The chloro-benzene phenanthro-of 3,4-dihydro-3-methyl-8-[3,2-c] furans-1,2-diketone (II-2)
The bromo-benzene phenanthro-of 3,4-dihydro-3-methyl-8-[3,2-c] furans-1,2-diketone (II-3)
The chloro-benzene phenanthro-of 3,4-dihydro-3-methyl-9-[3,2-c] furans-1,2-diketone (II-4)
The bromo-benzene phenanthro-of 3,4-dihydro-3-methyl-9-[3,2-c] furans-1,2-diketone (II-5)
3,4-dihydro-3-methyl-9-methoxyl group-benzene phenanthro-[3,2-c] furans-1,2-diketone (II-6)
3,4-dihydro-3-methyl-9-amino-benzene phenanthro-[3,2-c] furans-1,2-diketone (II-8)
3,4-dihydro-3-methyl-9-(N-2-methyl)-benzene phenanthro-[3,2-c] furans-1,2-diketone (II-9)
3,4-dihydro-3-methyl-9-acetylaminohydroxyphenylarsonic acid benzene phenanthro-[3,2-c] furans-1,2-diketone (II-10)
3,4-dihydro-3-methyl-9,10-dimethoxy-benzene phenanthro-[3,2-c] furans-1,2-diketone (II-11).
The code name of the compound in pharmacological testing is equal to the corresponding compound structure of code name herein below.
Compound of Formula I of the present invention can be standby in order to below legal system.
A. substituted phenylethylene reacts in solvent with 2-methoxyl group Isosorbide-5-Nitrae-para benzoquinone, obtains compound 3-methoxyl group-Isosorbide-5-Nitrae-phenanthrenequione compounds (3) after purifies and separates;
B. demethylating under compound (2) alkaline condition, obtains 3-hydroxyl-Isosorbide-5-Nitrae-phenanthrenequione compounds (4) after purifies and separates;
C. compound (4) reacts with monochloroacetone generation Feist-Benary, generates Tanshinone I compounds (6);
D. Tanshinone I analog derivative (6), through transition metal-catalyzed hydrogenation, obtains dihydrotanshinone compounds (6)
Wherein R
1definition as claimed in claim 1; R
3represent O, (CH
2)
nn=1 ~ 3 or R
3=0.
According to preparing the described method of compound (3) in claim 7, for Diels-Alder[4+2] annulation, this reacts according to frontier orbital theory, the highest track of filling (HOMO) of diene body (styrene derivatives) and dienophile (2-methoxyl group-1,4-para benzoquinone) minimum not filling track (LUMO) mutually mate, heating condition under there is the collaborative reversible reaction of bimolecular.Owing to not relating to intermediate-ion, free radical etc., thus react required activation energy relatively high (this means need to be higher temperature), but due to bimolecular concerted reaction, regioselectivity is better.
According to preparing the described method of compound (3) in claim 7, we are using styrene derivatives as diene body, owing to being the diene body of the common composition of exocyclic double bond and cyclic olefinic bond, so the difficulty that can predict mainly contains following 2 points:
1. in the time that D-A reaction occurs styrene derivatives, certainly will to destroy the aromatic ring structure of styrene derivatives.But well-known, in the time forming aromatic ring, MO energy will decline, while destroying aromatic ring, molecular orbital(MO) total energy is also by upper.This means in the time that vinylbenzene, as diene body, D-A reaction occurs, will not contain than other diene body of fragrance ingredient, as cyclopentadiene, more difficult reaction.Therefore, can predict, it will be very difficult that D-A reacts this step.
2. vinylbenzene is to be widely used in the polymerization single polymerization monomer of manufacturing macromolecular compound, therefore under comparatively high temps, polymerization will certainly occur, thereby reduces productive rate.And these 2 be proved by experiments.
According to preparing the described method of compound (3) in claim 7, in order to solve the excessively slow problem of speed of reaction, we attempt using pressure-resistant reaction device for container, and under airtight condition, heating is up to 200 degrees Celsius.Due to and the closed nature of reaction vessel, styrene derivatives cannot be overflowed, so reduced cinnamic waste.Meanwhile, the speed that temperature of reaction causes that significantly raises promotes the shortening greatly (table 1) that has caused the reaction times.
the screening of table 1.D-A reaction conditions
Note: toluene, 200 DEG C of backflows, refer to react under pressurizing device.
According to preparing the described method of compound (3) in claim 7, described pressure-resistant reaction device refers to is generally engaged in the usual means that synthetic field personnel understand, as autoclave, tube sealing etc.
According to preparing the described method of compound (3) in claim 7, described organic solvent is selected from one or more in toluene, dimethylbenzene, benzene, oil of mirbane, dioxane, tetrahydrofuran (THF), ethyl acetate, propyl acetate, isobutyl acetate, tert.-butyl acetate, ethyl formate, methyl alcohol, ethanol or propyl alcohol, preferred ion liquid, toluene and dimethylbenzene.Temperature of reaction room temperature ~ 300 DEG C, preferably 50 ~ 200 DEG C.
According to preparing the described method of compound (3) in claim 7, in D-A reaction, due to the existence of methoxyl group in substrate para benzoquinone, make to react and in addition process, have locational choice problem, the position that is methoxyl group may be in C2 position or C3 position, may generate thus two kinds of isomerss that difference is very little.There is generally dispute to the position of methoxyl group in academia always.Schmalle etc. [Cryst, 1986, C42:1039] have carried out X-ray analysis in 1986 to its synthetic a series of phenanthrenequione derivatives, and the methoxy substitution that result records most compounds is positioned at C2 position.The present invention, for confirming this result, has carried out X-ray analysis by the monocrystalline of the chloro-Isosorbide-5-Nitrae-phenanthrenequione of 3-methoxyl group-8-, and crystalline structure proves, the methoxy substitution of compound 7 occurs in C-2 position, is target product.
The single crystal structure of the chloro-Isosorbide-5-Nitrae-phenanthrenequione of 3-methoxyl group-8-
According to preparing the described method of compound (4) in claim 7, the condition of described demethylation is alkaline condition, applied alkali refers to and is generally engaged in synthetic field inorganic strong alkali that personnel understand and organic strong compound herein, comprises potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, sodium hydride, hydrolith, potassium cyanide, lower aliphatic sodium alkoxide, lower aliphatic potassium alcoholate, sodium carbonate, salt of wormwood etc.Reaction solvent is water, lower aliphatic alcohols or the mixture of the two.Temperature of reaction room temperature ~ 300 DEG C, preferably 50 ~ 150 DEG C.
Be Feist-Benary reaction according to preparing the described side of compound (6) in claim 7, reference [J.Med.Chem., 2006,49:5631-5634.], we select with monochloroacetone as α-halogenatedketone, in weakly alkaline solution acetic acid-Spirit of Mindererus, react.
According to preparing the described method of compound (7) in claim 7, transition metal can be selected from the palladium of nickel, palladium, carrier adsorption or the platinum of platinum and oxidation state, preferably Raney's nickel and palladium carbon.
The pharmacologically active test experiments of part of compounds is as follows:
Compound prepared by claim 1, the propagation of having carried out kinds of tumor cells suppresses research, and table 1 is listed the IC50 value of part of compounds to K562 cell.Compared with blank assay group, all there is decline in various degree in the OD value of respectively organizing medicine.Wherein, there is significant difference with blank group in the OD value of its effect 24h in the time of concentration 1 μ g/ml.Each group of medicine of different concns made to broken line graph at different time points to the inhibiting rate of cell.The inhibitory rate of cell growth of all compounds presents ascendant trend with the increase of concentration and the prolongation of time.Wherein, the inhibitory rate of cell growth of part of compounds in the time of 1 μ g/ml action intensity slightly lower than 1 μ g/ml arsenus acid group.
The IC50 value of table 1 part of compounds to K562 cell
The antitumor test of SMMC-7721 people's liver cancer model of nude mice bearing tumor: the SMMC-7721 cell of logarithmic phase, after 0.25% trysinization dispersion, cell counting, is adjusted to cell concn and prepared 4 × 10
7the cell suspension of individual/ml.Get BALBC/c nude mice in 4 ~ 6 week age, An Er iodine right fore oxter sterilization, the growth of subcutaneous vaccination SMMC-7721 cell suspension cell in nude mouse with become knurl situation.Inoculate the administration of dividing into groups next day, group is model control group, positive controls, trial-product group, 15 every group.Give respectively PBS solution, tested medicine 0.01mmol/kg, As
2o
31.2mg/kg, every day 1 time, continuous 2 weeks, after 3 weeks, de-nude mice neck is put to death, get knurl body and weigh, calculate tumour inhibiting rate, tumour inhibiting rate (%)=［ the average knurl weight of the average knurl weight/control group of 1-experimental group ］ × 100%.
The antitumor test of table 2 part of compounds to SMMC-7721 people's liver cancer model of nude mice bearing tumor
The pharmacological results shows, compound of Formula I and pharmacy acceptable salt thereof have restraining effect in various degree to Several Kinds of Malignancy, and therefore, compound of Formula I and pharmacy acceptable salt thereof can be clinically for the relevant clinical diseases of kinds of tumors.These illnesss comprise: various malignant tumours as, papillary carcinoma, gland cancer, cystadenocarcinoma, mixed carcinoma, transitional epithelium cancer, rodent cancer, liposarcoma, leiomyosarcoma, fibrosarcoma, rhabdosarcoma, angiosarcoma, lymphangiosarcoma, osteosarcoma, chondrosarcoma, synovial sarcoma, multiple shape colloid matricyte tumor, myeloblastoma, malignant schwannoma, ganglioneuroblastoma, meningosarcoma, Hokdkin disease, non Hodgkin's disaese leukemia, multiple myeloma, chorioepithelium cancer, malignant mole, spermocytoma, embryonal carcinoma, malignant teratoma, malignant melanoma back lipoma, facial hemangioma, leiomyoma of uterus etc., papilloma, as bladder head knurl, papilloma of penis etc., gi tract adenoma, thyroid tumor, adenoma of breast etc., cystadenoma of ovary.
A kind of for antineoplastic medicinal compositions, contain compound of Formula I or its pharmacy acceptable salt and pharmaceutically acceptable carrier.Described medicinal compositions can be dosage form conventional in the pharmaceuticies such as conventional tablet or capsule, slow releasing tablet or capsule, control slow releasing tablet or capsule, oral liquid, injection, emulsion.
Specific embodiment
Illustrate the present invention below by embodiment, but the present invention has more than the example being confined to below.
Embodiment mono-3-methoxyl group-8-methyl isophthalic acid, 4-phenanthrene dione
In autoclave, add successively 2-methoxyl group-Isosorbide-5-Nitrae-para benzoquinone (0.5mmol), o-methyl styrene (3mmol), separately adds appropriate toluene that the two is mixed, and sealing, does not add external pressure, is heated to 200 DEG C, stirring reaction 3h.TLC detection reaction is complete.Reaction solution is cooling, and silica gel chromatographic column separates, and developping agent is methylene dichloride: sherwood oil (2:5).Obtain orange solid 59mg, productive rate 65%.1H NMR ( CDCl3, 400 Hz, TMS ): δ2.744 (s,3H), 3.942 (s,3H), 6.147(s,1H), 7.474(d,1H,J=6.8Hz), 7.628(t,1H, J=16Hz), 8.224(d,1H,J=8.4Hz), 8.398(d,1H, J=9.2Hz), 9.401(d,1H, J=8.8Hz)。
This is consistent for the preparation method of embodiment bis-, three, four.
Embodiment 23,6,7-trimethoxy-Isosorbide-5-Nitrae-phenanthrene dione
Substrate is corresponding styrene derivatives and 2-methoxyl group-Isosorbide-5-Nitrae-para benzoquinone, obtains orange solid 107.4mg, productive rate 60%.1H NMR ( CDCl3, 400 Hz, TMS ): δ3.920(s,3H,OCH3), 4.051(s,3H,OCH3), 4.110(s,3H,OCH3), 6.102(s,1H,AR-H), 7.121(s,1H, AR-H), 7.952(d,1H, J=8.8Hz, AR-H), 8.11(d,1H, J=8.4Hz, AR-H), 9.145(s,1H, AR-H)。
Embodiment 33,6 ,-dimethoxy-Isosorbide-5-Nitrae-phenanthrene dione
Substrate is corresponding styrene derivatives and 2-methoxyl group-Isosorbide-5-Nitrae-para benzoquinone, obtains orange solid 120.5mg, productive rate 65%.
1H NMR ( CDCl
3, 400 Hz, TMS ): δ3.940(s,3H), 4.002(s,3H), 6.138(s,1H), 7.290(dd,1H,J=11.6Hz), 7.788(d,1H, J=9.2Hz), 8.064(d,1H, J=8.0Hz), 8.116(d,1H, J=8.4Hz),9.056 (d,1H,J=2.4Hz)。
Chloro-Isosorbide-5-Nitrae-the phenanthrene dione of embodiment tetra-3-methoxyl group-8-
Substrate is corresponding styrene derivatives and 2-methoxyl group-Isosorbide-5-Nitrae-para benzoquinone, obtains orange solid 54.5mg, productive rate 40%.1H NMR ( CDCl3, 400 Hz, TMS ): δ3.96（s,3H,-OCH3）, 6.19(s,1H,H-2,3), 7.66(t,1H,J=16.4Hz,H-6),7.75(d,1H,J=7.6Hz,H-7),8.32(d,1H,J=8.8Hz,H-10),8.73(d,1H,J=8.8Hz,H-9),9.51(d,1H,J=8.8Hz,H-5)。
Embodiment five 3-methoxyl group-6-acetylaminohydroxyphenylarsonic acid Isosorbide-5-Nitrae-phenanthrene diones
Substrate is corresponding styrene derivatives and 2-methoxyl group-Isosorbide-5-Nitrae-para benzoquinone, obtains orange solid 97.4mg, productive rate 66%.1H NMR ( CDCl3, 400 Hz, TMS ): δ2.290(s,3H,CH3), 3.920(s,3H,CH3), 6.153(s,1H,AR-H), 7.654(s,1H,NH), 7.893(d,1H,J=8.8Hz, AR-H), 8.138(d,1H J=8.4Hz, AR-H), 8.154(d,1H, J=8.4Hz, AR-H), 8.436(d,1H, J=8.4Hz, AR-H),9.244(s,1H, AR-H)。
Embodiment 63,8-dimethyl-benzene phenanthro-[3,2-c] furans-1,2-diketone (I-1)
In round-bottomed flask, add successively sodium hydroxide (2.1mmol), water (50ml), 3-methoxyl group-8-methyl isophthalic acid, 4-phenanthrene dione (0.4mmol) and dehydrated alcohol (3ml), mix, electric-heating cap reflux 1h, and TLC detection reaction is complete.Reaction solution is cooling, adjusts pH to 3 left and right with the hydrochloric acid soln of 0.5mol/L HCl, and ethyl acetate is extracted (20ml × 3), collects ethyl acetate layer, washing, anhydrous sodium sulfate drying, filters, concentrated, obtain dark red solid 95.3mg, productive rate 89%, reactant is directly used in next step reaction;
In round-bottomed flask, drop into successively previous step reactant, toluene 10ml, glacial acetic acid (2mmol), ammonium acetate (2mmol), monochloroacetone (2mmol), ethanol (2ml), 90 DEG C of reflux, lucifuge stirring reaction 2h, TLC detection reaction is complete.Reaction solution is cooling, adds the dilution of 70ml water, and ethyl acetate extraction (20ml × 3), collects ethyl acetate layer, washing, and anhydrous sodium sulfate drying, filters, concentrated.Silica gel chromatographic column separates, and developping agent is sherwood oil-methylene dichloride (3:1), obtains red solid 88.32 mg, productive rate 80%.
1HNMR (400MHz, CDCl
3) δ2.278(s,3H,CH3),2.667(s,3H,CH3), 7.282(s,1H,CH),7.326(d,1H,J=8.8Hz,AR-H),7.526( t, 1H, J= 16Hz, AR-H), 7.758(d, 1H, J= 8.8Hz, AR-H), 8.257(d,1H,J=8.8Hz,AR-H),9.216(d,1H,J=9.2Hz,AR-H). MS ( m/z ): 277.2 [M+H]
＋。
The embodiment seven chloro-benzene phenanthro-of 3-methyl-8-[3,2-c] furans-1,2-diketone (I-2)
Operation, with compound I-1, is replaced 3-methoxyl group-8-methyl isophthalic acid by corresponding compound, and 4-phenanthrene dione, obtains orange red solid 0.84g, and yield is 80%.。
1HNMR (400MHz, CDCl
3) δ: 2.276 ( 3H, s); 7.321 ( 1H, s); 7.345 (1H, d); 7.617 ( 1H ,m); 7.789 ( 1H, d); 8.406 ( 1H, d); 9.231 ( 1H, d). MS ( m/z ): 297.2 [M+H]
＋。
The embodiment eight bromo-benzene phenanthro-of 3-methyl-8-[3,2-c] furans-1,2-diketone (I-3)
Operation, with compound I-1, is replaced 3-methoxyl group-8-methyl isophthalic acid by corresponding compound, and 4-phenanthrene dione, obtains orange red solid 0.84g, and yield is 80%.。
1HNMR (400MHz, CDCl
3) δ: 2.269 ( 3H, s); 7.289 ( 1H, s); 7.352 (1H, d); 7.579 ( 1H ,m); 7.779 ( 1H, d); 8.317 ( 1H, d); 9.211 ( 1H, d). MS ( m/z ): 341.2 [M+H]
＋。
The embodiment nine chloro-benzene phenanthro-of 3-methyl-9-[3,2-c] furans-1,2-diketone (I-4)
Operation, with compound I-1, is replaced 3-methoxyl group-8-methyl isophthalic acid by corresponding compound, and 4-phenanthrene dione, obtains orange red solid 0.84g, and yield is 80%.。
1HNMR (400MHz, CDCl
3) δ: 2.272 ( 3H, s); 7.256 ( 1H, s); 7.315 (1H, d); 7.567 ( 1H ,d); 7.790 ( 1H, d); 8.153 ( 1H, d); 9.231 ( 1H, d). MS ( m/z ): 297.7 [M+H]
＋。
The embodiment ten bromo-benzene phenanthro-of 3-methyl-9-[3,2-c] furans-1,2-diketone (I-5)
Operation, with compound I-1, is replaced 3-methoxyl group-8-methyl isophthalic acid by corresponding compound, and 4-phenanthrene dione, obtains orange red solid 0.84g, and yield is 80%.
1HNMR (400MHz, CDCl
3) δ: 2.269 ( 3H, s); 7.285 ( 1H, s); 7.320 (1H, d); 7.558 ( 1H ,d); 7.767 ( 1H, d); 8.298 ( 1H, d); 9.224 ( 1H, d). MS ( m/z ): 341.2 [M+H]
＋。
Embodiment 11 3-methyl-9-methoxyl group-benzene phenanthro-[3,2-c] furans-1,2-diketone (I-6)
Operation, with compound I-1, is replaced 3-methoxyl group-8-methyl isophthalic acid by corresponding compound, and 4-phenanthrene dione, obtains orange red solid 0.89g, and yield is 80%.
1HNMR( 400MHz, CDCl
3) δ: 2.394 ( 3H, s); 4.040 (3H, s); 7.301 (1H, d); 7.518 ( 1H, s); 7.790 ( 1H, d); 8.110 ( 1H, dd), 8.966 ( 1H, dd); 9.283( 1H, d). MS (m/z): 293.1[M+H]
＋。
Embodiment 13 3-methyl-9-amino-benzene phenanthro-[3,2-c] furans-1,2-diketone (I-7)
Operation, with compound I-1, is replaced 3-methoxyl group-8-methyl isophthalic acid by corresponding compound, and 4-phenanthrene dione, obtains orange red solid 0.84g, and yield is 80%.MS( m/z ): 278.2 [M+H]
＋。
Embodiment 14 3-methyl-9-(N, N-dimethylamino)-benzene phenanthro-[3,2-c] furans-1,2-diketone (I-8)
Operation, with compound I-1, is replaced 3-methoxyl group-8-methyl isophthalic acid by corresponding compound, and 4-phenanthrene dione, obtains orange red solid 0.84g, and yield is 80%.
1HNMR( 400MHz, CDCl
3) δ: 1.808 ( 3H, s); 2.834( 6H, s); 6.976 ( 1H, s); 7.345( 1H, dd); 7.514( 1H, s)；7.854 ( 1H, d); 7.890 ( 1H, d); 9.012( 1H, d) ; MS( m/z): 306.3 [M+H]
＋。
Embodiment 15 3-methyl-9-acetylaminohydroxyphenylarsonic acid benzene phenanthro-[3,2-c] furans-1,2-diketone (I-9)
Operation, with compound I-1, is replaced 3-methoxyl group-8-methyl isophthalic acid by corresponding compound, and 4-phenanthrene dione, obtains orange red solid 0.84g, and yield is 80%.MS ( m/z ):306.3 [M+H]
＋。
Embodiment 16 3-methyl-9,10-dimethoxy-benzene phenanthro-[3,2-c] furans-1,2-diketone (I-10)
Operation, with compound I-1, is replaced 3-methoxyl group-8-methyl isophthalic acid by corresponding compound, and 4-phenanthrene dione, obtains orange red solid 0.62g, and yield is 50%.。
1HNMR( 400MHz, CDCl
3) δ: 2.416 ( 3H, s); 4.053 ( 3H, s); 4.130 (3H, s); 7.093 ( 1H, s); 7.489 ( 1H, s); 7.958 ( 1H, d); 8.122 ( 1H, d); 9.271 ( 1H, d). MS ( m/z ): 323.1[M+H]
＋。
Embodiment 17,4-dihydro-3,8-dimethyl-benzene phenanthro-[3,2-c] furans-1,2-diketone (III-1)
1. by 3-methyl-8-methyl-benzene phenanthro-[3; 2-c] furans-1; it is solvent that 2-diketone (I-1) (0.48g, 1.5mmol) uses toluene, adds the palladium charcoal (24mg) of 5% weight; hydrogen shield; 50 DEG C of stirrings, reaction overnight, filters; 25 DEG C of concentrating under reduced pressure obtain orange red solid 0.43g, and yield is 90%.(operating below identical)
1hNMR (400MHz, CDCl
3) δ: 1.648 (3H, d); 2.078 (1H, m); 2.667 (3H, s); 4.125 (2H, m); 7.326 (1H, d); 7.526 (1H, t); 7.758 (1H, d); 8.257 (1H, d); 9.216 (1H, d). MS (m/z): 279.2 [M+H]
+.
2. by 3-methyl-8-methyl-benzene phenanthro-[3; 2-c] furans-1; it is solvent that 2-diketone (I-1) (0.48g, 1.5mmol) uses toluene, adds the fresh Raney's nickel (36mg) of preparing of 5% weight; hydrogen shield; 50 DEG C of stirrings, reaction overnight, filters; 25 DEG C of concentrating under reduced pressure obtain orange red solid 0.43g, and yield is 90%.
Embodiment 18, the chloro-benzene phenanthro-of 4-dihydro-3-methyl-8-[3,2-c] furans-1,2-diketone (II-2)
Operation is identical with embodiment 27 preparation III-1.Obtain class redness, red solid yield is 90%.
1HNMR (400MHz, CDCl
3) δ:1.645（3H, d）; 2.125(1H, m); 2.276 ( 3H, s); 4.087(2H, m); 7.367 (1H, d); 7.545 ( 1H ,t); 7.834 ( 1H, d); 8.421 ( 1H, d); 9.010 ( 1H, d). MS ( m/z ): 299.7 [M+H]
＋
Embodiment 19, the bromo-benzene phenanthro-of 4-dihydro-3-methyl-8-[3,2-c] furans-1,2-diketone (II-3)
Operation is identical with preparation III-1.Obtain class redness, red solid yield is 93%.
1HNMR (400MHz, CDCl
3) δ: 1.698(3H, d); 2.245(1H, m); 2.269 ( 3H, s);4.245(2H, m); 7.334 (1H, d); 7.587 ( 1H ,t); 7.803 ( 1H, d); 8.307 ( 1H, d); 9.017 ( 1H, d). MS ( m/z ): 342.2 [M+H]
＋。
Embodiment 20, the chloro-benzene phenanthro-of 4-dihydro-3-methyl-9-[3,2-c] furans-1,2-diketone (II-4)
Operation is identical with preparation III-1.Obtain redness, red solid yield is 90%.
1HNMR (400MHz, CDCl
3) δ: 1.681(3H, d); 2.145(1H, m); 2.271 ( 3H, s); 4.065(2H, m); 7.304 (1H, d); 7.346 ( 1H ,t); 7.651 ( 1H, d); 8.567 ( 1H, d); 9.132 ( 1H, d). MS ( m/z ): 299.1 [M+H]
＋。
Embodiment 21, the bromo-benzene phenanthro-of 4-dihydro-3-methyl-9-[3,2-c] furans-1,2-diketone (II-5)
Operation is identical with preparation III-1.Obtain redness, red solid yield is 90%.
1HNMR (400MHz, CDCl
3) δ:1.687(1H, d); 2.087(1H, m); 2.269 ( 3H, s);4.128(2H, m); 7.423 (1H, d); 7.542 ( 1H ,m); 7.457 ( 1H, d); 8.108 ( 1H, d); 9.197 ( 1H, d). MS ( m/z ): 342.2 [M+H]
＋。
Embodiment 22,4-dihydro-3-methyl-9-methoxyl group-benzene phenanthro-[3,2-c] furans-1,2-diketone (II-6)
By 3-methyl-9-methoxyl group-benzene phenanthro-[3,2-c] furans-1,2-diketone (0.48g, 1.5mmol), adds the palladium charcoal (48mg) of 10% weight, hydrogen shield, and 50 DEG C of stirrings, reaction overnight, filters, and it is 90% that 25 DEG C of concentrating under reduced pressure obtain orange red solid yield.
1HNMR( 400MHz, CDCl
3) δ: 1.694(3H, d); 2.056(1H, m); 4.012(2H, m) 4.149 (3H, s); 7.321 (1H, d); 7.821 ( 1H, d); 8.164 ( 1H, dd), 8.175 ( 1H, dd); 9.012( 1H, d). MS(m/z): 295.4 [M+H]
＋。
Embodiment 24,4-dihydro-3-methyl-9-amino-benzene phenanthro-[3,2-c] furans-1,2-diketone (II-7)
Operation is identical with preparation III-1.Obtain redness, red solid yield is 92%.1.564 ( 3H, d);2.156(1H, m) 2.834( 6H, s); 4.132(2H, m), 4.808 ( 2H, s); 6.076 ( 1H, s); 7.345( 1H, d); 7.854 ( 1H, d); 7.890 ( 1H, d); 9.012( 1H, d) ; MS( m/z ): 280.2 [M+H]
＋。
Embodiment 25,4-dihydro-3-methyl-9-(N, N-methylamino)-benzene phenanthro-[3,2-c] furans-1,2-diketone (II-8)
Operation is identical with preparation III-1.Obtain redness, red solid yield is 94%.
1HNMR( 400MHz, CDCl
3) δ: 1.564 ( 3H, d);2.12 (1H, m) 2.834( 6H, s); 3.945(2H, m), 6.823 ( 1H, s); 7.219( 1H, d); 7.831 ( 1H, d); 7.926 ( 1H, d); 9127( 1H, d); MS ( m/z ): 308.3 [M+H]
＋。
Embodiment 26,4-dihydro-3-methyl-9-acetylaminohydroxyphenylarsonic acid benzene phenanthro-[3,2-c] furans-1,2-diketone (II-9)
Operation is identical with preparation III-1.Obtain redness, red solid yield is 91%.Operation, with compound I-1, obtains orange red solid 0.62g, and yield is 50%.。
1HNMR( 400MHz, CDCl
3) δ:1.702（3H, d）; 2.046(1H, m) ; 2.416 ( 3H, s); 4.053 ( 3H, s); 4.130 (3H, s); 7.093 ( 1H, s); 7.489 ( 1H, s); 7.958 ( 1H, d); 8.122 ( 1H, d); 9.271 ( 1H, s). MS ( m/z ): 322.3 [M+H]
＋。
Embodiment 27,4-dihydro-3-methyl-9,10-dimethoxy-benzene phenanthro-[3,2-c] furans-1,2-diketone (II-10)
Operation is identical with preparation III-1.Obtain redness, red solid yield is 87%.δ: 1.675(3H, d) ; 2.097(1H, m), 2.425 ( 3H, s); 3.987 ( 2H,m);4.068 (3H, s); 4.130 (3H, s); 7.123 ( 1H, s); 7.990 ( 1H, d); 8.122 ( 1H, d); 9.317 ( 1H, s).MS ( m/z ): 325.1[M+H]
＋。
Embodiment 38 cell toxicity tests
Liquid preparation and grouping
It is appropriate that precision takes the synthetic tanshinone Ⅰ derivative obtaining, DMSO dissolves, be mixed with certain density storing solution, before dosing, with RPMI-1640 nutrient solution (containing 10% deactivation class standard foetal calf serum, 100 U/ml penicillin, 100 μ g/ml Streptomycin sulphates), (in each medicine group of 8.0 μ g/ml, DMSO final concentration is 0.03% to be diluted to respectively the liquid that final concentration is 0.5,1.0,2.0,4.0,6.0,8.0 μ g/ml, while it is generally acknowledged DMSO≤0.1%, do not cause that cytobiology form changes).Experiment is taking arsenus acid as reference medicine (final concentration is 1 μ g/ml).Each group liquid is all prepared under aseptic condition, crosses 0.22 μ m millipore filtration degerming before dosing.
Cell cultures and dosing regimen
Getting human leukaemia K562 is suspended in 10-12 ml RPMI-1640 nutrient solution (containing 10% deactivation class standard foetal calf serum, 100 U/ml penicillin, 100 μ g/ml Streptomycin sulphates), at 37 DEG C, 5% CO
2, saturated humidity incubator in cultivate, every other day pour out old nutrient solution and change fresh culture.The cell in vegetative period (cell survival rate is greater than 97%) of taking the logarithm, adding appropriate nutrient solution to adjust cell density is 5 × 10
4individual/ml; Get 96 orifice plates, add wherein respectively each group of medicine and the reference medicine of 20 μ l different concns, 80 μ l cell suspensions are inoculated in every hole subsequently, and each experimental group is established 6 multiple holes.Experiment arranges blank group, adds wherein 80 μ l cell suspensions and 20 μ l RPMI-1640 nutrient solutions, and one group of RPMI-1640 nutrient solution group is set as zeroing group.
Embodiment 39
Get in embodiment seven 0.5 gram of the compound of preparation, 3.0 grams of starch, 0.8 gram, dextrin, 0.2 gram of Microcrystalline Cellulose, makes wetting agent, granulation, compressing tablet with appropriate 25% ethanol.
Claims (10)
1. a preparation method for Tanshinone I analog derivative, it is prepared by the following method:
Substituted phenylethylene (
1) and 2-methoxyl group Isosorbide-5-Nitrae-para benzoquinone (
2) in solvent through D-A reaction cyclization, after purifies and separates compound (
3); Compound (
3) demethylating under alkaline condition, after purifies and separates compound (
4); Compound (
4) react to obtain Tanshinone I compounds with monochloroacetone generation Feist-Benary;
Wherein, R
1~ R
4represent hydrogen, chlorine, bromine, iodine, fluorine, methoxyl group, oxyethyl group, allyloxy, amino, the monosubstituted amido of C1 ~ C4 alkyl, C1 ~ C4 alkyl bis substituted amine base, 1-morpholinyl, piperidyl, kharophen, guanidine radicals, nitro, trifluoromethyl, cyano group, ethanoyl, C1 ~ C4 alkyl sulphonyl, amino-sulfonyl, C1 ~ C4 alkylamino radical alkylsulfonyl, allyl amido alkylsulfonyl, morpholine-1-base alkylsulfonyl.
2. method according to claim 1, wherein, substituted phenylethylene (
1) and 2-methoxyl group Isosorbide-5-Nitrae-para benzoquinone (
2) in solvent through D-A reaction cyclization obtain compound (
3) concrete reaction vessel be autoclave, tube sealing; Temperature of reaction is room temperature ~ 300 DEG C.
3. method according to claim 2, temperature of reaction is 50 ~ 200 DEG C.
4. method according to claim 2, described solvent is selected from one or more in toluene, dimethylbenzene, benzene, oil of mirbane, dioxane, tetrahydrofuran (THF), ethyl acetate, propyl acetate, isobutyl acetate, tert.-butyl acetate, ethyl formate, methyl alcohol, ethanol or propyl alcohol.
5. method according to claim 2, described solvent is selected from ionic liquid, toluene, dimethylbenzene.
6. method according to claim 1, described alkaline condition alkali used is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium hydride, sodium carbonate, salt of wormwood.
7. method according to claim 6, described alkali is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide.
8. method according to claim 1, the reaction solvent of described demethylation is water.
9. method according to claim 1, the temperature of reaction of described demethylation is room temperature ~ 300 DEG C.
10. method according to claim 9, described temperature of reaction is 50-150 DEG C.
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| Antitumor Agents. 239. Isolation, Structure Elucidation, Total Synthesis, and Anti-Breast Cancer Activity of Neo-tanshinlactone from Salvia miltiorrhiza;Xihong Wang, et al.;《Journal of Medicinal Chemistry》;20041012;第47卷(第23期);第5816-5819页 * |
| Cancer Chemopreventive Activities of S-3-1, A Synthetic Derivative of Danshinone;Xiao-Guang Chen, et al.;《Journal of Asian Natural Products Research》;20011231;第3卷(第1期);第63-75页 * |
| Xiao-GuangChen et al..Cancer Chemopreventive Activities of S-3-1 |
| Xihong Wang, et al..Antitumor Agents. 239. Isolation, Structure Elucidation, Total Synthesis, and Anti-Breast Cancer Activity of Neo-tanshinlactone from Salvia miltiorrhiza.《Journal of Medicinal Chemistry》.2004,第47卷(第23期),第5816-5819页. |
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